Endoglin is a transmembrane glycoprotein, found is association with members of the TGF-beta superfamily receptors, that is implicated in angiogenesis, vessel wall homeostasis and pathobiology. Mutations in the endoglin gene result in hereditary hemorrhagic telangiectasia type 1 (HHT1), a vascular disorder characterized by multi-systemic vascular dysplasia, arteriovenous malformations, and focal dilation of post- capillary venules. Endoglin is expressed at high levels response to vessel injury. Endoglin null mice appear to have normal vasculogenesis, however, loss of endoglin results in defective angiogenesis and altered vascular smooth muscle development. We provide preliminary data showing that endoglin expression is altered in the response to vascular injury in vivo, both in endothelial cells and VSMC. We also provide data that suggest that endoglin expression in VSMCs has functional consequences in vitro. An important question, therefore, is whether VSMCs, or an indirect effect of neighboring endothelial cells that lack endoglin. The central hypothesis we wish to test is that endoglin expression in both ECs and VSMCs is required for normal angiogenesis and vessel wall integrity. We propose to employ EC- and VSMC-specific Cre recombinase control of endoglin expression to address clinical sequelae seen in heterozygous endoglin null adult mice, is due to the absence (or reduction) of endoglin expression in VSMCs, ECs, or both. Though endoglin associates with members of the TGF-beta superfamily receptors, the mechanism of endoglin function remains elusive. The second aim of this proposal seeks to determine the biological significance of a novel protein zyxin, may interact with the endoglin-L isoform cytosolic domain (CD). Therefore, we wish to examine the hypothesis that the endoglin-L CD plays a role in the mechanism of endoglin function. This proposal seeks, therefore, to determine the relevance of endoglin-protein interactions to the mechanism of endoglin function. We suggest that the application of conditional expression techniques to the study of endoglin function in vivo and in vitro may provide a unique opportunity to gain insight into the mechanism of angiogenesis, and the processes underlying vessel remodeling, and the pathobiology of HHT1 and arteriovenous malformation.